Cannabinoid derivatives

Abstract

This disclosure relates generally to cannabinoid derivatives having the formula (I), wherein R4 is hydrogen, —C(Q1)N(R4a)(R4b) or —C(R4J)(R4k)N(R4e)C(0)R4f, R6 is hydrogen, —C(Q2)N(R6a)(R6b) or —C(R6J)(R6k)N(R6e)C(0)R6f, provided that R6 is not hydrogen when R4 is hydrogen. Pharmaceutical compositions for the prevention or treatment of a disease associated with a cannabinoid receptor (such as CB1 or CB2) in a subject in need thereof, and methods of using the cannabinoid derivatives are also described.

1 - 124 . (canceled) 
     
     
         125 . A compound having structural formula: 
       
         
           
           
               
               
           
         
       
       or an enantiomer, diastereomer, racemate, tautomer, or metabolite thereof, or a pharmaceutically acceptable salt, a solvate or hydrate of the compound, enantiomer, diastereomer, racemate, tautomer, or metabolite, wherein
 the 
 
       
         
           
           
               
               
           
         
       
       moiety is 
       
         
           
           
               
               
           
         
         R 1a  and R 1b  are independently
 hydrogen, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, hydroxy, halo, —O(C 1 -C 4  alkyl), —C(O)(C 1 -C 4  alkyl), —CO 2 H, —CO 2 (C 1 -C 4  alkyl), —(C 0 -C 4 —(C 0 -C 4  alkyl)-heteroaryl, —(C 0 -C 4  alkyl)-cycloalkyl, —(C 0 -C 4  alkyl)-heterocycloalkyl, or —NR 1c R 1d  wherein 
 R 1c  and R 1d  are independently hydrogen, C 1 -C 4  alkyl, or —C(O)(C 1 -C 4  alkyl), or R 1a  and R 1b  together with a carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl ring; 
 
         R 2  is hydrogen, halo, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, —CO 2 H, —(C 0 -C 4  alkyl)-C(O)O(C 1 -C 6  alkyl), —(C 0 -C 4  alkyl)-OC(O)O—(C 1 -C 6  alkyl), —OR 2a , —(C 1 -C 4  alkyl)OR 2a , —SR 2a , —(C 1 -C 4 alkyl)SR 2a , —NR 2b R 2c , —(C 1 -C 4  alkyl)NR 2b R 2c , —(C 1 -C 4  alkyl)C(O)NR 2b R 2c , —(C 0 -C 4  alkyl)-aryl, —(C 0 -C 4  alkyl)-heteroaryl, —(C 0 -C 4  alkyl)-cycloalkyl, —(C 0 -C 4  alkyl)-heterocycloalkyl, or oxo when attached to a ring of appropriate saturation, wherein
 R 2a , R 2b , and R 2c  are independently hydrogen, C 1 -C 4  alkyl, or —C(O)(C 1 -C 4 ) alkyl; 
 
         R 3  is hydrogen, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, —(OCH 2 CH 2 ) 0-6 O(C 1 -C 8  alkyl), —(C 0 -C 4  alkyl)-NR 3a R 3b , —(C 0 -C 4  alkyl)-aryl, —(C 0 -C 4  alkyl)-heteroaryl, —(C 0 -C 4  alkyl)-cycloalkyl or —(C 0 -C 4  alkyl)-heterocycloalkyl, wherein R 3a  and R 3b  are each independently hydrogen or C 1 -C 6  alkyl; 
         R 4  is hydrogen, 
       
       
         
           
           
               
               
           
         
       
       wherein
   Q 1  is O or S;   R 4a  is hydrogen, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, —OR 4c , —(C 1 -C 4 alkyl)OR 4c , —(C 0 -C 4  alkyl)-C(O)(C 1 -C 4  alkyl), —(C 0 -C 4 alkyl)-C(O)O(R 4c ), —(C 0 -C 4  alkyl)CN, —(CH 2 CH 2 O) 0-6 (C 1 -C 8  alkyl), —(CH 2 CH 2 O) 0-6 (NR 4c R 4d ), —(C 1 -C 4 alkyl)NR 4c R 4d , —(C 0 -C 4  alkyl)-aryl, —(C 0 -C 4  alkyl)-heteroaryl, —(C 0 -C 4  alkyl)-cycloalkyl, or —(C 0 -C 4  alkyl)-heterocycloalkyl,   R 4b  is hydrogen, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, —OR 4c , —(C 1 -C 4 alkyl)OR 4c , —(C 0 -C 4  alkyl)-C(O)(C 1 -C 4  alkyl), —(C 0 -C 4 alkyl)-C(O)O(R 4c ), —(C 0 -C 4  alkyl)CN, —(CH 2 CH 2 O) 0-6 (C 1 -C 8  alkyl), —(CH 2 CH 2 O) 0-6 (NR 4c R 4d ), —(C 1 -C 4 alkyl)NR 4c R 4d , —(C 0 -C 4  alkyl)-aryl, —(C 0 -C 4  alkyl)-heteroaryl, —(C 0 -C 4  alkyl)-cycloalkyl, or —(C 0 -C 4  alkyl)-heterocycloalkyl,
 wherein R 4c  and R 4d  are hydrogen or C 1 -C 6  alkyl, 
   or R 4a  and R 4b  together with a nitrogen to which they are attached form a heterocycloalkyl or heteroaryl ring;   R 4e  is hydrogen, C 1 -C 8  alkyl, cycloalkyl, or aryl,   R 4f  is —OR 4g , C 1 -C 8  alkyl, cycloalkyl, or NR 4h R 4i ,
 wherein R 4g  is C 1 -C 8  alkyl, cycloalkyl, or aryl, and 
 wherein R 4h  and R 4i  are C 1 -C 8  alkyl, or R 4h  and R 4i  together with a nitrogen to which they are attached form a heterocyloalkyl ring or heteroaryl ring, and 
   R 4j  and R 4k  are each independently hydrogen or C 1 -C 8  alkyl;   
 R 5  is hydrogen, C 1 -C 8  alkyl, —(C 1 -C 4  alkyl)-O—(C 1 -C 4  alkyl), —C(O)(C 1 -C 4  alkyl), —C(O)O(C 1 -C 4  alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 4  alkyl), —C(O)N(C 1 -C 4  alkyl) 2 , —(C 1 -C 4  alkyl)C(O)O(C 1 -C 4  alkyl), or —(C 1 -C 4  alkyl)OC(O)(C 1 -C 4  alkyl); 
 R 6  is hydrogen, 
 
       
         
           
           
               
               
           
         
       
       provided that R 6  is not hydrogen when R 4  is hydrogen, wherein
   Q 2  is O or S;   R 6a  is hydrogen, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, —OR 6c , —(C 1 -C 4 alkyl)OR 6c , —(C 0 -C 4  alkyl)-C(O)(C 1 -C 4  alkyl), —(C 0 -C 4 alkyl)-C(O)O(R 6c ), —(C 0 -C 4  alkyl)CN, —(CH 2 CH 2 O) 0-6 (C 1 -C 8  alkyl), —(CH 2 CH 2 O) 0-6 (NR 6c R 6d ), —(C 1 -C 4 alkyl)NR 6c R 6d , —(C 0 -C 4  alkyl)-aryl, —(C 0 -C 4  alkyl)-heteroaryl, —(C 0 -C 4  alkyl)-cycloalkyl, or —(C 0 -C 4  alkyl)-heterocycloalkyl,   R 6b  is hydrogen, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, —OR 6c , —(C 1 -C 4 alkyl)OR 6c , —(C 0 -C 4  alkyl)-C(O)(C 1 -C 4  alkyl), —(C 0 -C 4 alkyl)-C(O)O(R 6c ), —(C 0 -C 4  alkyl)CN, —(CH 2 CH 2 O) 0-6 (C 1 -C 8  alkyl), —(CH 2 CH 2 O) 0-6 (NR 6c R 6d ), —(C 1 -C 4 alkyl)NR 6c R 6d , —(C 0 -C 4  alkyl)-aryl, —(C 0 -C 4  alkyl)-heteroaryl, —(C 0 -C 4  alkyl)-cycloalkyl, or —(C 0 -C 4  alkyl)-heterocycloalkyl,
 wherein R 6c  and R 6d  are hydrogen or C 1 -C 6  alkyl, 
 or R 6a  and R 6b  together with a nitrogen to which they are attached form a heterocycloalkyl or heteroaryl ring, 
   R 6e  is hydrogen, C 1 -C 8  alkyl, cycloalkyl, or aryl,   R 6f  is —OR 6g , C 1 -C 8  alkyl, cycloalkyl, or NR 6h R 6i ,
 wherein R 6g  is C 1 -C 8  alkyl, cycloalkyl, or aryl, and 
 wherein R 6h  and R 6i  are C 1 -C 8  alkyl, or R 6h  and R 6i  together with a nitrogen to 
 which they are attached form a heterocyloalkyl ring or heteroaryl ring, and 
   
 R 6j  and R 6k  are each independently hydrogen or C 1 -C 8  alkyl; 
 
       wherein
 each alkyl, alkenyl and alkynyl is unsubstituted, halogenated, or substituted with one or two hydroxyl groups, one or two C 1 -C 6  alkoxy groups, one or two —C(O)O(C 1 -C 4  alkyl) groups, or one or two oxo groups; 
 each cycloalkyl has 3-10 ring carbons and is saturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings, each fused ring having 3-8 ring members, and is substituted with 0-6 R 7 ; 
 each heterocycloalkyl has 3-10 ring members and 1-3 heteroatoms where each is independently nitrogen, oxygen or sulfur and is saturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings, each having 3-8 ring members, and is substituted with 0-6 R 7 ; 
 each aryl is a phenyl or a naphthyl, and optionally includes one or two fused cycloalkyl or heterocycloalkyl rings, each fused cycloalkyl or heterocycloalkyl ring having 4-8 ring members, and is substituted with 0-5 R 8 ; 
 each heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms, where each is independently nitrogen, oxygen or sulfur or a 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms where each is independently nitrogen, oxygen or sulfur, and optionally includes one or two fused cycloalkyl or heterocycloalkyl rings, each fused cycloalkyl or heterocycloalkyl ring having 4-8 ring members, and is substituted with 0-5 R 8 , 
 in which
 each R 7  is independently oxo, C 1 -C 4  alkyl, —Cl, —F, —Br, —CN, —SF 5 , —N 3 , nitro, —SR A , —S(O) 1-2 R A , —OR A , —(C 0 -C 3  alkyl)-OR B , —C(O)R A , —C(O)NR B R A , —NR B C(O)R A , —C(S)NR B R A , —NR B C(S)R A , —CO 2 R A , —OC(O)R A , —C(O)SR A , —SC(O)R A , —C(S)OR A , —OC(S)R A , —C(S)SR A , —SC(S)R A , —S(O) 1-2 OR A , —OS(O) 1-2 R A , —S(O) 1-2 NR B R A , —NR B S(O) 1-2 R A , —OCO 2 R A , —OC(O)NR B R A , —NR B CO 2 R A , —NR B C(O)NR B R A , —SCO 2 R A , —OC(O)SR A , —SC(O)SR A , —SC(O)NR B R A , —NR B C(O)SR A , —OC(S)OR A , —OC(S)NR B R A , —NR B C(S)OR A , —NR B C(S)NR B R A , —SC(S)OR A , —OC(S)SR A , —SC(S)SR A , —SC(S)NR B R A , —NR B C(S)SR A , —NR B C(NR B )NR B R A , —NR B S(O) 1-2 NR B R A , phenyl, C 3 -C 8  cycloalkyl, a five to six-membered heteroaryl, or a five to six-membered heterocycloalkyl; 
 each R 8  is independently optionally-substituted C 1 -C 4  alkyl, —Cl, —F, —Br, —CN, —SF 5 , —N 3 , nitro, —SR A , —S(O) 1-2 R A , —OR A , —(C 0 -C 3  alkyl)-OR B , —NR B R A , —C(O)R A , —C(O)NR B R A , —NR B C(O)R A , —C(S)NR B R A , —NR B C(S)R A , —CO 2 R A , —OC(O)R A , —SO 3 H, —C(O)SR A , —SC(O)R A , —C(S)OR A , —OC(S)R A , —C(S)SR A , —SC(S)R A , —S(O) 1-2 OR A , —OS(O) 1-2 R A , —S(O) 1-2 NR B R A , —NR B S(O) 1-2 R A , —OCO 2 R A , —OC(O)NR B R A , —NR B CO 2 R A , —NR B C(O)NR B R A , —SCO 2 R A , —OC(O)SR A , —SC(O)SR A , —SC(O)NR B R A , —NR B C(O)SR A , —OC(S)OR A , —OC(S)NR B R A , —NR B C(S)OR A , —NR B C(S)NR B R A , —SC(S)OR A , —OC(S)SR A , —SC(S)SR A , —SC(S)NR B R A , —NR B C(S)SR A , —NR B C(NR B )NR B R A , —NR B S(O) 1-2 NR B R A , unsubstituted phenyl, or a five to six-membered unsubstituted heteroaryl; 
 
 wherein each R A  is independently hydrogen or C 1 -C 3  alkyl, and each R B  is independently hydrogen, C 1 -C 3  alkyl, C 1 -C 3  fluoroalkyl, C 1 -C 3  hydroxyalkyl, —S(O) 1-2 (C 1 -C 3  alkyl), —C(O)(C 1 -C 3  alkyl) or —CO 2 (C 1 -C 3  alkyl); and 
 
       provided the compound is not:
 3-(1-hydroxy-6,6-dimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamido)propanoic acid, 
 3-(1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamido)propanoic acid, 
 N-(2-(2-(aminomethoxy)ethoxy)ethyl)-1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7, 8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide, or 
 N-(3-amino-5-nitrophenyl)-1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide. 
 
     
     
         126 . The compound according to  claim 125 , wherein the moiety 
       
         
           
           
               
               
           
         
       
     
     
         127 . The compound according to  claim 125 , wherein R 1a  and R 1b  are each independently hydrogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, hydroxy, halo, —O(C 1 -C 4  alkyl), —C(O)(C 1 -C 4  alkyl), —CO 2 (C 1 -C 4  alkyl), —(C 0 -C 4  alkyl)-aryl, —(C 0 -C 4  alkyl)-heteroaryl, —(C 0 -C 4  alkyl)-cycloalkyl or —(C 0 -C 4  alkyl)-heterocycloalkyl. 
     
     
         128 . The compound according to  claim 125 , wherein R 2  is hydrogen, halo, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, —CO 2 H, —(C 0 -C 4  alkyl)-C(O)O(C 1 -C 6  alkyl), —OR 2a , —(C 1 -C 4  alkyl)OR 2a , —SR 2a , —(C 1 -C 4  alkyl)SR 2a , —NR 2b R 2c , —(C 1 -C 4  alkyl)NR 2b R 2c , —(C 1 -C 4  alkyl)C(O)NR 2b R 2c , —(C 0 -C 4  alkyl)-aryl, —(C 0 -C 4  alkyl)-heteroaryl, —(C 0 -C 4  alkyl)-cycloalkyl, —(C 0 -C 4  alkyl)-heterocycloalkyl, or oxo. 
     
     
         129 . The compound according to  claim 125 , wherein R 3  is hydrogen, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, C 2 -C 12  alkynyl, —(OCH 2 CH 2 ) 0-6 OCH 3 , —(C 0 -C 4  alkyl)-aryl, —(C 0 -C 4  alkyl)-heteroaryl, —(C 0 -C 4  alkyl)-cycloalkyl or —(C 0 -C 4  alkyl)-heterocycloalkyl. 
     
     
         130 . The compound according to  claim 125 , wherein R 5  is hydrogen, C 1 -C 6  alkyl, —(C 1 -C 4  alkyl)-O—(C 1 -C 4  alkyl), —C(O)(C 1 -C 4  alkyl), —C(O)O(C 1 -C 4  alkyl), —C(O)NH 2 , —C(O)NH(C 1 -C 4  alkyl), or —C(O)N(C 1 -C 4  alkyl) 2 . 
     
     
         131 . The compound according to  claim 125 , wherein R 6  is hydrogen. 
     
     
         132 . The compound according to  claim 125 , wherein the compound is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         133 . The compound according to  claim 125 , wherein Q 1  is O. 
     
     
         134 . The compound according to  claim 125 , wherein Q 1  is S. 
     
     
         135 . The compound according to  claim 125 , wherein R 4a  is hydrogen, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, —OR 4c , —(C 1 -C 4 alkyl)OR 4c , —(C 0 -C 4  alkyl)-C(O)(C 1 -C 4  alkyl), —(C 0 -C 4 alkyl)-C(O)O(R 4c ), —(C 0 -C 2  alkyl)CN, —(CH 2 CH 2 O) 0-4 (C 1 -C 8  alkyl), —(CH 2 CH 2 O) 0-6 (NR 4c R 4d ), —(C 1 -C 4 alkyl)NR 4c R 4d , —(C 0 -C 4  alkyl)-aryl, —(C 0 -C 4  alkyl)-heteroaryl, —(C 0 -C 4  alkyl)-cycloalkyl, or —(C 0 -C 4  alkyl)-heterocycloalkyl, wherein R 4c  and R 4d  are hydrogen or C 1 -C 4  alkyl, and R 4b  is hydrogen or C 1 -C 6  alkyl, or R 4a  and R 4b  together with a nitrogen to which they are attached form a heterocycloalkyl or heteroaryl ring. 
     
     
         136 . The compound according to  claim 125 , wherein R 4b  is hydrogen or C 1 -C 8  alkyl. 
     
     
         137 . The compound according to  claim 125 , wherein each alkyl is unsubstituted. 
     
     
         138 . The compound according to  claim 125 , wherein each R 7  is independently oxo, C 1 -C 4  alkyl, —Cl, —F, —Br, —CN, —SF 5 , —N 3 , nitro, —SR A , —S(O) 1-2 R A , —OR A , —NR B R A , —C(O)R A , —C(O)NR B R A , —NR B C(O)R A , —C(S)NR B R A , —NR B C(S)R A , —CO 2 R A , —OC(O)R A , —C(O)SR A , —SC(O)R A , —C(S)OR A , —OC(S)R A , —C(S)SR A , —SC(S)R A , —S(O) 1-2 OR A , —OS(O) 1-2 R A , —S(O) 1-2 NR B R A , or —NR B S(O) 1-2 R A . 
     
     
         139 . The compound according to  claim 125 , wherein each R 8  is independently C 1 -C 4  alkyl, —Cl, —F, —Br, —CN, —SF 5 , —N 3 , nitro, —SR A , —S(O) 1-2 R A , —OR A , —NR B R A , —C(O)R A , —C(O)NR B R A , —NR B C(O)R A , —C(S)NR B R A , —NR B C(S)R A , —CO 2 R A , —OC(O)R A , —C(O)SR A , —SC(O)R A , —C(S)OR A , —OC(S)R A , —C(S)SR A , —SC(S)R A , —S(O) 1-2 OR A , —OS(O) 1-2 R A , —S(O) 1-2 NR B R A , or —NR B S(O) 1-2 R A . 
     
     
         140 . The compound according to  claim 125 , which is:
 1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N-methoxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   N-ethyl-1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N-isopropyl-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   N-acetyl-1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   N-cyclopropyl-1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   N-cyclopentyl-1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-6,6,9-trimethyl-3-pentyl-N-(1-(trifluoromethyl)cyclopentyl)-6H-benzo[c]chromene-2-carboxamide;   N-cyclohexyl-1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-6,6,9-trimethyl-3-pentyl-N-phenyl-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N-(4-methoxyphenyl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-6,6,9-trimethyl-3-pentyl-N-(4-(trifluoromethyl)phenyl)-6H-benzo[c]chromene-2-carboxamide;   N-(2,6-dimethylphenyl)-1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   N-benzyl-1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-6,6,9-trimethyl-3-pentyl-N-(pyridin-3-ylmethyl)-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-6,6,9-trimethyl-3-pentyl-N-(pyrimidin-5-ylmethyl)-6H-benzo[c]chromene-2-carboxamide;   N-(3,4-dimethylisoxazol-5-yl)-1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-6,6,9-trimethyl-N-(oxazol-5-ylmethyl)-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   N-((1,3,4-oxadiazol-2-yl)methyl)-1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   N-((1H-tetrazol-5-yl)methyl)-1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   methyl (1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carbonyl)glycinate;   methyl (1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carbonyl)-L-alaninate;   methyl (1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carbonyl)-L-phenylalaninate;   methyl (1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carbonyl)-L-histidinate;   N-allyl-1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N,N,6,6,9-pentamethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   N-cyclopropyl-1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   N-cyclohexyl-1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-N-phenyl-6H-benzo[c]chromene-2-carboxamide;   N-benzyl-1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-N-(pyridin-3-ylmethyl)-6H-benzo[c]chromene-2-carboxamide;   N-((1H-tetrazol-5-yl)methyl)-1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N-(isoxazol-3-ylmethyl)-N,6,6,9-tetramethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   (5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-2-yl)methanone;   (1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-2-yl)(4-methylpiperazin-1-yl)methanone;   1-(4-(1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carbonyl)piperazin-1-yl)ethan-1-one;   (1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-2-yl)(4-(methylsulfonyl)piperazin-1-yl)methanone;   (1,1-dioxidothiomorpholino)(1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-2-yl)methanone;   (1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-2-yl)(morpholino)methanone;   methyl (1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carbonyl)-D-prolinate;   (1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-2-yl)(pyrrolidin-1-yl)methanone;   1-(1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carbonyl)pyrrolidin-3-one;   (1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-2-yl)(isoindolin-2-yl)methanone;   (1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-2-yl)(1H-indol-1-yl)methanone;   aziridin-1-yl(1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-2-yl)methanone;   (S)-(1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-2-yl)(2-methylaziridin-1-yl)methanone;   (R)-(1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-2-yl)(2-methylaziridin-1-yl)methanone;   azetidin-1-yl(1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-2-yl)methanone;   (3,3-difluoroazetidin-1-yl)(1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-2-yl)methanone;   N,N-diethyl-1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   N-cyano-1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N-methoxy-N,6,6,9-tetramethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   N-allyl-1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N-(2-methoxyethyl)-N,6,6,9-tetramethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   N-(2-(dimethylamino)ethyl)-1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N,N-bis(2-hydroxyethyl)-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   N-(2-bromobenzyl)-1-hydroxy-6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N,6,6,9-tetramethyl-3-propyl-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N-methoxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   N-ethyl-1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N-isopropyl-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   N-acetyl-1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   N-cyclopropyl-1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   N-cyclopentyl-1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-6,6,9-trimethyl-3-pentyl-N-(1-(trifluoromethyl)cyclopentyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   N-cyclohexyl-1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-6,6,9-trimethyl-3-pentyl-N-phenyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N-(4-methoxyphenyl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-6,6,9-trimethyl-3-pentyl-N-(4-(trifluoromethyl)phenyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   N-(2,6-dimethylphenyl)-1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   N-benzyl-1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-6,6,9-trimethyl-3-pentyl-N-(pyridin-3-ylmethyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-6,6,9-trimethyl-3-pentyl-N-(pyrimidin-5-ylmethyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   N-(3,4-dimethylisoxazol-5-yl)-1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-6,6,9-trimethyl-N-(oxazol-5-ylmethyl)-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   N-((1,3,4-oxadiazol-2-yl)methyl)-1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]ch-romene-2-carboxamide;   N-((1H-tetrazol-5-yl)methyl)-1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   methyl 2-(1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamido)acetate;   (2S)-methyl 2-(1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamido)propanoate;   (2S)-methyl 2-(1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamido)-3-phenylpropanoate;   (2S)-methyl 2-(1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamido)-3-(1H-imidazol-5-yl)propanoate;   N-allyl-1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N,N,6,6,9-pentamethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   N-cyclopropyl-1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   N-cyclohexyl-1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-N-phenyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   N-benzyl-1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-N-(pyridin-3-ylmethyl)-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   N-((1H-tetrazol-5-yl)methyl)-1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N-(isoxazol-3-ylmethyl)-N,6,6,9-tetramethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   (5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-2-yl)methanone;   (1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-2-yl)(4-methylpiperazin-1-yl)methanone;   1-(4-(1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carbonyl)piperazin-1-yl)ethan-1-one;   (1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-2-yl)(4-(methylsulfonyl)piperazin-1-yl)methanone;   (1,1-dioxidothiomorpholino)(1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-2-yl)methanone;   methyl (1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carbonyl)-D-prolinate;   (1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-2-yl)(pyrrolidin-1-yl)methanonel;   1-(1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carbonyl)pyrrolidin-3-one;   (1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-2-yl)(i soindolin-2-yl)methanone;   (1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-2-yl)(1H-indol-1-yl)methanone;   aziridin-1-yl(1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-2-yl)methanone;   (1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-2-yl)((S)-2-methylaziridin-1-yl)methanone;   (1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-2-yl)((R)-2-methylaziridin-1-yl)methanone;   azetidin-1-yl(1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-2-yl)methanone;   (3,3-difluoroazetidin-1-yl)(1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-2-yl)methanone;   N,N-diethyl-1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   N-cyano-1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N-methoxy-N,6,6,9-tetramethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   N-allyl-1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N-(2-methoxyethyl)-N,6,6,9-tetramethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   N-(2-(dimethylamino)ethyl)-1-hydroxy-N,6,6,9-tetramethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   1-hydroxy-N,N-bis(2-hydroxyethyl)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide;   N-(2-bromobenzyl)-1-hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide; or   1-hydroxy-N,6,6,9-tetramethyl-3-propyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxamide.   
     
     
         141 . A compound that is selected from compounds 1a-58a and 1b-58b. 
     
     
         142 . A pharmaceutical composition comprising a compound of  claim 125 , or an enantiomer, diastereomer, racemate, tautomer, or metabolite thereof, or a pharmaceutically acceptable salt, solvate or hydrate of the compound, enantiomer, diastereomer, racemate, tautomer, or metabolite, together with a pharmaceutically acceptable excipient, diluent, or carrier. 
     
     
         143 . A method of treating a disease associated with a cannabinoid receptor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to  claim 125  or a pharmaceutical composition thereof. 
     
     
         144 . A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to  claim 125  or a pharmaceutical composition thereof, wherein the disease is acute pain, ADHD/ADD, alcohol use disorder, allergic asthma, ALS, Alzheimer's, anorexia, anxiety disorders, social anxiety disorder, specific phobia, test anxiety, generalized anxiety disorder, arthritis, atherosclerosis, autism, bipolar disorder, burns, cancer, cancer pain, Charcot-Marie-Tooth disease, chronic inflammatory demyelinating polyneuropathies, chronic pain, chronic allograft nephropathy, cocaine use disorder, complex regional pain syndrome, congestive heart failure, depression, fibromyalgia, fragile X syndrome/FXTAS, frontotemporal dementias, gingivitis pyrexia, glaucoma, glioblastoma, glomerulonephropathy, Huntington's disease, hypertrophic scars, IBD/IBS, inflammation, Inflammatory myopathies, ischemia, kidney fibrosis, keloids, leukodystrophies, liver fibrosis, liver cirrhosis, lung fibrosis, migraine, multiple sclerosis, myocardial infarction, nausea, CINV, motion sickness, neuropathic pain, postherpetic neuralgia, painful diabetic neuropathy, nightmare disorder, non-alcoholic fatty liver disease, obesity, obsessive-compulsive disorder, opioid sparing, opioid use disorder, osteoarthritis, osteoporosis, Parkinson's, post-concussion syndrome/traumatic brain injury, psychosis/schizophrenia, PTSD, regulation of bone mass, REM sleep behaviour disorder, reperfusion injury, Rett syndrome, rheumatoid arthritis, skin conditions, acne, psoriatic arthritis, sleep disorders, insomnia, RLS, spinocerebellar ataxias, systemic fibrosis, systemic sclerosis, thermal injury, tobacco use disorder/nicotine dependence, Tourette's, tumors, or trigeminal neuralgia. 
     
     
         145 . A method of treating a disease associated with a cannabinoid receptor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to  claim 141  or a pharmaceutical composition thereof. 
     
     
         146 . A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to  claim 141  or a pharmaceutical composition thereof, wherein the disease is acute pain, ADHD/ADD, alcohol use disorder, allergic asthma, ALS, Alzheimer's, anorexia, anxiety disorders, social anxiety disorder, specific phobia, test anxiety, generalized anxiety disorder, arthritis, atherosclerosis, autism, bipolar disorder, burns, cancer, cancer pain, Charcot-Marie-Tooth disease, chronic inflammatory demyelinating polyneuropathies, chronic pain, chronic allograft nephropathy, cocaine use disorder, complex regional pain syndrome, congestive heart failure, depression, fibromyalgia, fragile X syndrome/FXTAS, frontotemporal dementias, gingivitis pyrexia, glaucoma, glioblastoma, glomerulonephropathy, Huntington's disease, hypertrophic scars, IBD/IBS, inflammation, Inflammatory myopathies, ischemia, kidney fibrosis, keloids, leukodystrophies, liver fibrosis, liver cirrhosis, lung fibrosis, migraine, multiple sclerosis, myocardial infarction, nausea, CINV, motion sickness, neuropathic pain, postherpetic neuralgia, painful diabetic neuropathy, nightmare disorder, non-alcoholic fatty liver disease, obesity, obsessive-compulsive disorder, opioid sparing, opioid use disorder, osteoarthritis, osteoporosis, Parkinson's, post-concussion syndrome/traumatic brain injury, psychosis/schizophrenia, PTSD, regulation of bone mass, REM sleep behaviour disorder, reperfusion injury, Rett syndrome, rheumatoid arthritis, skin conditions, acne, psoriatic arthritis, sleep disorders, insomnia, RLS, spinocerebellar ataxias, systemic fibrosis, systemic sclerosis, thermal injury, tobacco use disorder/nicotine dependence, Tourette's, tumors, or trigeminal neuralgia.